There is increasing evidence that heredity plays a role in the development of alcoholism. The proposed research will examine some of the genetic antecedents of alcoholism in the American Indian population. While major research initiatives aimed at identifying the genes associated with alcoholism have begun in the Caucasian population, these studies largely exclude the Indian peoples. Among Orientals a single gene mutation has been identified which decreases alcohol intake. The mutation is a single base pair substitution that renders the enzyme aldehyde dehydrogenase (ALDH) inactive. Orientals with this gene develop a syndrome following alcohol ingestion with facial flushing, tachycardia and some nausea. While the mutation is common in Oriental populations (approx. 45%) it is seen in a very low proportion (approx. 4%) of Oriental alcoholics. Thus, it would appear that ALDH deficiency provides some immunity against the development of alcoholism. It is assumed that American Indians should show a similar frequency of this mutation, due to lineage to the Mongoloid race. The flushing reaction in Indians has long been assumed to occur. However, this has been documented in only a single report in 1972. While some researchers have found from 2-16% of various Indian tribes phenotypically deficient in ALDH, others have failed to find any American Indians with the ALDH deficiency. In pilot work we have identified some American Indians who self-report flushing reactions upon ingestion of ethanol. Thus, the nature of and the frequency of the flushing response in American Indians is not known. In addition, the relationship between ALDH activity and drinking levels has not been studied in American Indians. To investigate the possibility that American Indians have a genetic defect in the metabolism of alcohol we will: 1) Examine the qualitative and quantitative aspects of the flushing response to ingested alcohol by monitoring skin temperature, heart rate, blood pressure, blood acetaldehyde and alcohol levels in flushing and non-flushing American Indians as well as in Oriental and Caucasian control subjects. 2) Determine the phenotypic level of ALDH activity in flushing and non-flushing individuals from the three racial groups. 3) Determine whether or not American Indians have mutations in the genes which code for the alcohol metabolizing enzymes alcohol dehydrogenase (ADH) and ALDH. 4) Determine the interrelationships between the flushing response, ALDH activity, the rate of alcohol clearance, blood acetaldehyde levels, genotype of ADH and ALDH, the quantity/frequency of alcohol drinking behavior and family history of alcoholism through multivariate statistical techniques. 5) In the second year determine the population frequencies of the various ADH and ALDH geneotypes in several western Indian tribes (Blackfeet, Sioux, Navaho). The relationships between genotype, self-reported flushing, drinking practices and family history of alcoholism will be determined.